Public opinion guidance plays a crucial role in the management of major public health incidents, and thus, exploring its mechanism is conducive to the comprehensive governance of social security. This study conducts a case study on the anti-pandemic public opinion guidance and analyzes the public opinion representation and the internal mechanism of public opinion guidance in the context of the COVID-19 in China. The findings suggest that the public opinion on the COVID-19 manifested a three-stage progressive and stable tendency and witnessed the strength of China, specifically, benefiting from the systematic and complete integration and release mechanism for anti-pandemic information, the three-dimensional mechanism for the dissemination of knowledge related to pandemic prevention and health, the innovative disclosure mechanism for precise information, and diversified channels for international public opinion guidance. The guidance mechanism proposed in this study provides significant suggestions for the public opinion guidance of global major public health incidents in future.